CN1630709A - 人胰高血糖素样多肽-1模拟物和它们在治疗糖尿病和相关状况中的应用 - Google Patents
人胰高血糖素样多肽-1模拟物和它们在治疗糖尿病和相关状况中的应用 Download PDFInfo
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- CN1630709A CN1630709A CNA028205588A CN02820558A CN1630709A CN 1630709 A CN1630709 A CN 1630709A CN A028205588 A CNA028205588 A CN A028205588A CN 02820558 A CN02820558 A CN 02820558A CN 1630709 A CN1630709 A CN 1630709A
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- ethyl
- phe
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- 238000011282 treatment Methods 0.000 title claims abstract description 18
- 206010012601 diabetes mellitus Diseases 0.000 title claims description 13
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 title abstract description 4
- 101500028774 Homo sapiens Glucagon-like peptide 1 Proteins 0.000 title abstract 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 214
- 230000000694 effects Effects 0.000 claims abstract description 13
- -1 heterocyclic radical Chemical class 0.000 claims description 771
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 354
- 229910052731 fluorine Inorganic materials 0.000 claims description 353
- 239000011737 fluorine Substances 0.000 claims description 353
- 229960005190 phenylalanine Drugs 0.000 claims description 241
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 240
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 claims description 210
- 239000001301 oxygen Substances 0.000 claims description 164
- 229910052760 oxygen Inorganic materials 0.000 claims description 164
- 125000000217 alkyl group Chemical group 0.000 claims description 158
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 148
- 229910052799 carbon Inorganic materials 0.000 claims description 135
- 125000000539 amino acid group Chemical group 0.000 claims description 124
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims description 117
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- 125000003118 aryl group Chemical group 0.000 claims description 76
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 67
- 125000001072 heteroaryl group Chemical group 0.000 claims description 65
- 238000000034 method Methods 0.000 claims description 63
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 59
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- 150000001413 amino acids Chemical class 0.000 claims description 38
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 38
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 36
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- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 35
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- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 33
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 33
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 31
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 31
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 31
- 125000000623 heterocyclic group Chemical group 0.000 claims description 29
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 27
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 27
- 239000000460 chlorine Substances 0.000 claims description 26
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 26
- HYOWVAAEQCNGLE-SNVBAGLBSA-N (2r)-2-azaniumyl-2-methyl-3-phenylpropanoate Chemical compound [O-]C(=O)[C@@]([NH3+])(C)CC1=CC=CC=C1 HYOWVAAEQCNGLE-SNVBAGLBSA-N 0.000 claims description 25
- HYOWVAAEQCNGLE-JTQLQIEISA-N alpha-methyl-L-phenylalanine Chemical compound OC(=O)[C@](N)(C)CC1=CC=CC=C1 HYOWVAAEQCNGLE-JTQLQIEISA-N 0.000 claims description 25
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- 125000002252 acyl group Chemical group 0.000 claims description 24
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
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- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 20
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 claims description 20
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Natural products C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 19
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- 229910052740 iodine Inorganic materials 0.000 claims description 18
- 239000011630 iodine Substances 0.000 claims description 18
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 17
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 17
- 239000004473 Threonine Substances 0.000 claims description 16
- 125000004171 alkoxy aryl group Chemical group 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- 125000003368 amide group Chemical group 0.000 claims description 16
- 125000004104 aryloxy group Chemical group 0.000 claims description 16
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 16
- 229960002898 threonine Drugs 0.000 claims description 16
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 14
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 13
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 claims description 13
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 12
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- 125000004423 acyloxy group Chemical group 0.000 claims description 12
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- 125000003275 alpha amino acid group Chemical group 0.000 claims description 12
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- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 12
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- 125000002947 alkylene group Chemical group 0.000 claims description 11
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 11
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- 125000000769 L-threonyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](O[H])(C([H])([H])[H])[H] 0.000 claims description 10
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 10
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 claims description 10
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
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- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 claims description 7
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CN115697968B (zh) * | 2020-05-28 | 2024-03-29 | 杭州中美华东制药有限公司 | (s)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基丙酸甲酯及其盐的制备方法 |
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CA2463908A1 (en) | 2003-04-24 |
JP2005514337A (ja) | 2005-05-19 |
BR0213377A (pt) | 2006-05-23 |
US20100210552A1 (en) | 2010-08-19 |
EP1572892A4 (en) | 2007-08-22 |
NZ531788A (en) | 2008-01-31 |
US7238670B2 (en) | 2007-07-03 |
US20070287670A1 (en) | 2007-12-13 |
ZA200402846B (en) | 2005-08-16 |
PL377687A1 (pl) | 2006-02-06 |
KR20040054729A (ko) | 2004-06-25 |
HRP20040343A2 (en) | 2005-08-31 |
WO2003033671A3 (en) | 2005-12-29 |
RU2353625C2 (ru) | 2009-04-27 |
IS7185A (is) | 2004-03-16 |
NO20041203L (no) | 2004-06-10 |
WO2003033671A2 (en) | 2003-04-24 |
GEP20063908B (en) | 2006-08-25 |
EP1572892A2 (en) | 2005-09-14 |
US20030195157A1 (en) | 2003-10-16 |
HUP0700151A2 (en) | 2007-05-29 |
IL160917A0 (en) | 2004-08-31 |
YU31004A (sh) | 2006-08-17 |
AU2002348469B2 (en) | 2008-03-13 |
RU2004114836A (ru) | 2005-04-10 |
MXPA04003553A (es) | 2004-07-22 |
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